Anticonvulsant succinimide



United States Patent F 2,993,835 ANTICONVULSANT SUCCINIMIDE Charles A. Miller, Detroit, and 'Loren M. Long, Grosse Pointe Woods, Mich., assignors to Parke, Davis &

Company, Detroit, Mich., a corporation of Michigan N Drawing. Filed Oct. 27, 1958, Ser. No. 769,582

9 Claims. (Cl. 167-65) The present invention relates to anticonvulsant compositions useful in the treatment of epilepsy, and to methods for the prevention of convulsions and epileptic attacks by the use of these compositions.

More particularly, the present invention relates to therapeutic compositions which contain as an active ingredient a-ethyl-u-methy1snccinimide of the formula and to methods for the use of such therapeutic compositions.

The compositions and methods of this invention are characterized by their high therapeutic effect with freedom from undesirable side-effects, by their ability to control epileptic seizures not amenable to other forms of therapy, and by their continued effectiveness when they are employed over prolonged periods of time. In these respects the present invention provides substantial advantages over the prior art.

It is known that epilepsy is a pathological condition involving the central nervous system. This condition is arbitrarily divided into three main types according to the type of seizure which takes place in the patient. These types include grand mal, petit mal, and psychomotor seizures. A patient may have any of the above seizures or a mixture of any of the types.

Experimentally, the eifectiveness of a drug for protec tion against grand mal seizures is determined by its ability to raise the electroshock threshold in animals (usually mice or cats). The eifectiveness of a product against petit mal seizures is determined experimentally by the use of the so-called anti-pentamethylenetetrazole test or anti- Metrazol test which is based on the fact that the epileptic foci which give rise to petit mal attacks are situated in the region where pentamethylenetetrazole exerts its convulsive activity. Consequently, a product which will prevent seizures caused by pentamethylenetetrazole will also prevent a great many of the petit mal type of seizures. There is no satisfactory experimental method for the testing of drugs possessing the ability to control psychomotor seizures.

In the human patient the products used in the treatment.

5,5-diphenylhydantoin but these compounds have little effect on the petit mal and psychomotor types ofseizures.

2,993,835 Patented July 25, 1961 2 achieved in the treatment of petit mal seizures by the use of selected succinirnides. Certain members of the succinimide series such as N-methyl-u-phenylsuccinimide and N-methyl-a-methyl-a-phenylsuccinimide have achieved wide acceptance in clinical medicine by virtue oftheir high therapeutic activity with minimal side-effects. However, the known succinimide therapeutic compositions, while they have in many cases achieved high levels of success in the prevention and control of petit mal seizures, have in other cases failed to produce a satisfactory result.

Thus, while it can be said that Nnnethyl-a-phenylsuccinimide and N-methyl-amethyl-a-phenylsuccinimide are drugs of choice in the present-day treatment of epilepsy by virtue of their significant therapeutic effect with minimal toxicity in a majority of petit mal cases, it is nevertheless true that a substantial residuum of petit mal cases remains unbenefited by these drugs or by any other known form of treatment. Furthermore, the drugs which are presently used in the treatment of epilepsy, including both succinimide, and non-succinimide compositions, possess the general disadvantage of failing to maintain their initial therapeutic effect over a prolonged period of medication. That is, many cases are found where a particular patient initially obtains a complete prevention or substantial reduction in petit mal seizures on a particular medication, but, after continuation of the medication over 'a period of a few months or a few years, the eifectiveness of the drug is substantially diminished. To the extent that drugs pres ently used in the treatment of epilepsy are incapable of maintaining their full efiectiveness over a prolonged period of time they are deficient in the properties desired in a product of this type since epilepsy is a chronic condition which must be treated over a period of years.

One of the objects of the present invention is to provide compositions for the treatment of the petit mal type of epilepsy which are more effective than the compositions now in use for this purpose, and to provide compositions for the treatment of other types of epileptic seizures, both alone and in combination with petit mal seizures.

Another object of this invention is to provide compositions for the prevention of epileptic seizures which are therapeutically eifective in cases where the known'anticonvulsants, including the presently accepted succinimide compositions, have failed to produce clinically .satisfactory results.

A further object of theinvention is to provide compositions for the prevention of epileptic seizures which retain a high degree of efiectivenessand continue to produce an adequate therapeutic response over a prolonged period of medication.

Still another object of this invention is to provide methods for the prevention of epileptic seizures by the use of a-ethyl-a-methylsuccinimide. In accordance with the invention, these as well as other objects which will appear hereinafter are realized by the manufacture and use of compositions containing a-ethyl-oa- Petit mal seizures have been treated with substituted, 2,4-oxazolidinediones such as 3,5,5-trimethyl-2,4-oxazol- However, the usefulness of methylsuccinimide, alone or in combination with other ingredients.

a-Ethyl-u-methylsuccinimide is known in the prior art as a chemical entity, having been prepared according to the method described by Sircar, J. Chem. Soc., 128:600

-(1927), and characterized in J. Chem. Soc., 12811254 (1927).

However, its efiicacy as a therapeutic agent has heretofore been unknown.

The high degree of eifectiveness of a-ethyl-a-methylsuccinimide in controlling petit mal seizures can be demonstrated by results reported by Zimmerman and Burgemeist er on a group of 109 cases of petit mal epilepsy. For the most part, this group of cases consisted of patients who had not responded satisfactorily to the other anticonvulsant drugs. Medication was administered initially at adose of 250 toSOO mg. per day with a gradual increase in the dosage over a period of weeks until the optimal efiect was achieved or toxic side-effects intervened. The average daily dose for this group of patients was 1.75 g. The results obtained are summarized 'in Table 1. TABLE 1 Effectiveness of a-ethyl-a-methylsuccinimide in controlling or reducing petit mal attacks in a group of 109 patients generally resistant to drug therapy Avg. dura- Range of N0. of Percent of tion of Control Patients Patients Treatment (weeks) (weeks) Complete Control 46 42 44 12-96 Practical Control (80-99% reduction). 26 24 82 71-89 Partial Control (5- 79% reduction) 28 26 43 18-49 N Effect (04% reduction) 7 6 34 20-43 Worse (increase) 2 2 7 3-20 It is therefore seen that in this series of mostly intractable cases, complete control was secured in 42% of the patients, practical control was reached in an additional 24% and partial control in an additional 26% giving a total of 92% of all patients treated who received a measurable benefit from the drug.

Confirmation of the high activity of the a-ethyl-a- Degree of control achieved in petit mal cases receiving no help from N-methyl-a-methyl-a-phenylsuccinimide which responded favorably to a-ethyl-a-methylsuccinimide immediately thereafter N -methyl-a-methyl-aa-Ethyl-a-methylsucphenylsuccinimide cinjmide No. Percent No. Percent Complete Controh.-. 0 0 3 43 Practical Control (80-99% reduction). 0 0 2 28. 5 Partial Control (5- 79% reduction) 0 O 2 28. 5 No efiect (04% reduction) or Worse (increase) 7 100 0 0 methylsuccinimide is found in a group of 20 cases re- 3 ported by Strobos. These patients were afflicted with petit mal epilepsy alone and in combination with other types of seizures. Medication was administered to this group of patients at a dosage range from 0.75 to 2.0 g. per day.

The results obtained are summarized in Table 2.

TABLE 2 Efiectiveness of a-ethyl-a-methylsuccinimide in a group of 20 petit mal patients Effect on Seizures N o. of Percent of Patients Patients Controlled 10 50 3 2 1O 5 0 0 It is therefore seen that Whereas N-methyl-a-methyl-aphenylsuccinimide and a-ethyl-u-methylsuccinimide are structually related compounds, their pharmacological differences are not mere difierences of degree, but rather are difierences which set them apart as therapeutic agents.

The distinctive character of wethyLa-methylsuccinimide as an anticonvulsive agent is also found in the studies of Strobos and of Hughes, both of whom find petit mal patients completely controlled by this form of therapy, who had benefited little or not at all by previously used anticonvulsive agents. 1

The relative effectiveness of a-ethyl-a-methylsuccinimide in patients having pure petit mal attacks or more complex syndromes can be demonstrated by Table 4 wherein there are summarized results reported by Zim merman and Burgemeister in the same group of 109 cases reported in Table 1, but broken down into types. For the purpose of this classification, the following defini tions are applied:

(1) Pure petit mail: that form of epilepsy which manitests itself in loss of consciousness only with no coneomitant motor phenomena.

(2) Mixed petit mal: that form of epilepsy which manifests itself predominantly in transient loss of consciousness and minor motor phenomena. i

TABLE 4 Relative efiectiveness of a-ethyl-a-methylsuccinimide in the treatment of petit mal attacks in 109 patients having various classes of seizures Pure Petit Pure Petit Pure Petlt Mixed Petit Pure Petit Mixed Petit Mal and Mel, Grand Mal Only Mal Only Mal and Mal and Psycho- Mal, and

Grand Mal Grand Mal motor Psychomotor No Per- N 0. Per- No. Per- No Per- No Per- No. Percent cent cent cent cent cent Complete Control 11 61 5 21 17 59 9 35 2 29 2 40 Practical Control (-99% reduction 4 22 8. 5 9 31 9 35 1 14 1 20 Partial Control (549% reduction 8 17 14 58 2 7 3 l1 4 57 2 40 No Eflect (ll-4% reduction)..- 0 0 2 8. 5 1 3 4 15 0 0 0 0 Worse (increase) 0 0 1 4 0 0 1 4 0 0 0 0 Total 18 24 29 26 7 5 It is seen from these results that a-ethyl-a-methylsuccinimide is more effective in the treatment of pure petit mal than in the treatment of mixed petit mal and certain other classes of seizures.

In a series of 56 patients, all of whom had been treated previously with other drugs with, generally unsatisfactory results, Vossen has reported the superior activity and high selectivity of a-ethyl-a-methylsuccinimide on petit mal attacks. Strobos has likewise reported results which demonstrate the selective action of ot-ethyla-methylsuccinimide on idiopathic and particularly petit mal seizures, but which indicate little effect on iocal seizures or seizures resulting from brain damage. A classification of the 20 cases reported in Table 2 according to the type of seizure is summarized in Table 5.

TABLE 5 Relative effectiveness of u-ethyl-u-methylsuccinimide in the treatment of 20 patients havingva-rious classes of seizures including a petit mal component Grand Mal and Petit Mal and Akinetic Grand Mal and Petlt Mal Only Petit Mal Percent Per- 0 cent No. Percent Controlled; a 6 42 1 Subsfiaratially contro e Some Reduction... N 0 Effect Total TABLE 6 Nature and incidence of toxic side-efiects of a-ethyl-amethylsuccinimide in a group of 109 patients Side efifect:

Drowsiness Dizziness Nausea Gastric distress No. of patients unto-ts It was further observed that toxic side-efiects usually occurred on relatively high dosage levels and could be reduced or eliminated entirely by a reduction in dosage.

It has already been indicated that presently accepted anti-epileptic agents possess the common disadvantage that they fail to continue to produce their maximum therapeutic response when medication is continued over a prolonged period of time. In contrast, the administration of u-ethyl-a-methylsuccinirnide is accompanied by an increasing effectiveness upon prolonged treatment. The opposite effects obtained with a-ethyl-u-methylsuccinirnide and with other anticonvulsants including other succinimide compositions such as N-rnethyl-a-p'henylsuccinimide and N-methyl-a-methyl-a-phenylsuccinimide are illustrated in Table 7.

TABLE 7 Effectiveness of anticonvulsant drugs upon prolonged medication Complete Control for 6 1110s., 1 yr., 1% yrs, 2 yrs., I percent percent percent percent Phenobarbital 22 17 11 8 Trimethadione 36 34 31 28 N-methyl-a-phenylsucc mide 30 27 24 21 N-methyl-a-methyl-a-phenylsuceinimide 22 20 19 19 a-ethyl-a-methylsucclnimlde. 28 34 39 42 In this table, the criterion for effectivenes of each drug is defined as the percentage of patients completely protected against seizures. It will be observed that for each of tour standard anticonvulsants the percentage. of patients so protected steadily drops as medication is continued for a period of upto two years whereas in the case of a-ethyl-a-methylsuccinimide the percentage of patients so benefited substantially increases over the same interval of time. It is again seen that ot-ethyl-a-methylsuccinimide exhibits pharmaceutical properties which are differentiated in kind rather than in degree from other anticonvulsants.

. According to the present invention, anticonyulsant compositions are produced by constituting a-ethyl-amethylsuccinimi-de in edosa ge unit (form with pharmaceutical carriers or diluents. Dosage unit forms for oral administration are particularly suitable and for this purpose the a-ethyl-a-rnethylsuccinimide can be incorporated into tablets, powders, capsules, solutions, suspensions and similar forms. The medicament can be incorporated with phammaceutically-acceptable solid or liquid diluents. Solid carriers and diluents suitable for use include sugars such as lactose and sucrose; cellulose derivatives such as sodium carboxymcthyl cellulose, ethyl cellulose, methyl cellulose, and cellulose acetate phthalate; gelatin (including hard and soft gelatin capsules); talc; corn starch; stearic acid and magnesium stearate. Liquid carriers and diluents suitable for use include vegetable oils such as peanut oil, cottonseed o'il, sesame oil, olive oil, corn oil and oil of theobroma; polyethylene glycol; propylene glycol; glycerin; sorbitol; ethanol and water. The compound is quite soluble in water and aqueous solutions of approximately 20% concentration can be prepared; Suitable preservatives and flavoring agents can also be incorporated in such compositions. If administration by a parenteral route is desired, the medicament can also be prepared in solution or suspension in ampoule form by admixture with a liquid diluent. Other therapeutic agents and, in particular, other anticonyulsants can be incorporated with the u-ethyl-u-methylsuccinimide in these compositions. t

The percentage of ot-ethyl-a-methylsuccinimide in the compositions can be varied within wide limits. However, tor practical purposes, it is desirable that this compound be present in a concentration of at least 5% and the most satisfactory compositions are those in which a much higher proportion of this ingredient is present.

According to the methods of this invention, a-ethyl-amethylsuccinimide or compositions containing the same are administered for the prevention and control of epileptic seizures. The substances are commonly administered orally to provide a total daily dose of about 0.1 to 5.0 g. of the compound, optionally in divided portions. The dose is adjusted within the indicated range to the needs of the individual patient by first administering a daily dose of about 0.1 to 0.5 g. and then increasing the dose until satisfactory control of seizures is obtained or undesirable side-efiects intervene. In terms of individual patients, a satisfactory daily oral dose is usually found within the range of 5 mg. to mg. per kg. of body weight.

In the preparation of dosage unit forms such as tablets and capsules, the quantity of medicament furnished by each individual tablet or capsule is relatively unimportant since the indicated total daily dose can be reached by administering either one or a plurality of the tablets or capsules. However, for convenience in manufacturing and ease of administration it is preferable that such dosage forms contain at least 25 mg. and up to 500 mg. of a-ethyl-a-methylsuccinimide per unit.

The invention is illustrated but not limited by the following examples: EXAMPLE 1 u-Ethyl-a-methylsuccinimide is constituted into 500 mg. dosage units by encapsulation without anadjuvantinto hard gelatin capsules. The yield from 1,000 g. of a-ethyl-a-methylsuccinimide is about 1980 capsules, each containing 0.5 g. of medicament.

' EXAMPLE 2 An intimate mixture of 750 g. of a-ethyl-a-methylsuccinirnide and 750 g. of powdered milk sugar is constituted into dosage unit form by encapsulating the mix-' ture in 0.5 g. portions into hard gelatin capsules. The yield is about 2970 capsules each containing 250 mg. of a-ethyl-a-methylsuccinimide. If desired, the mixture can also be encapsulated in the so-called soft gelatin capsules. Also, if desired, the hard gelatin capsules can be sealed with a band of gelatin or other adhesive material.

, EXAMPLE 3 A tableting formulation is prepared as follows:

540 grains a-ethyl-a-methylsuccinimide 5 ounces, 87 grains powdered sugar with 3% starch 7 grains sodium saccharin U.S.P.

500 grains corn syrup q.s. water 88 grains ta-lc U.S.P. powdered Italian 18 grains magnesium stearate q.s. alcohol 8 min. oil spearmint terpeneless The formulation is compressed into tablets each containing 100 mg. of a-ethyl-a-methylsuccinimide. The yield is about 320-350 tablets.

EXAMPLE 4.

A tableting formulation providing a smaller dosage unit is prepared as follows:

'162 grains of a-ethyl-a-methylsuccinimide 5 ounces, 87 grains powdered sugar with 3% starch 7 grains sodium saccharin U.S.P.

500 grains corn syrup q.s. water 88 grains talc U.S.P. powdered Italian 18 grains magnesium stearate q.s. alcohol 8 min. oil spearmint terpeneless This formulation is compressed with a tableting machine to form tablets each containing 30 mg. of u-ethylu-methylsuccim'mide. The yield is about 320-350 tablets.

EXAMPLE 5 i a-ethyl-a-methylsuccinimide (500 g.) is dissolved in12 liters of water following which 4,000 g. of sucrose and 2,000 g. of sorbitol are dissolved in the solution. Oil of orange (30 ml.) and sodium benzoate (20 g.) are then added. The resulting solution is filtered, diluted to 20' liters with water and filled into bottles each containing ml. This aqueous solution, which is suitable for oraladministration, contains 25 mg. of ot-ethyl-a-methylsuc-i cinimide per ml.

This is a continuation-in-part of copending application Serial No. 311,798, filed September 26, 1952, now abandoned.

What is claimed is:

1. A composition in dosage unit form for the treatment of epilepsy comprising about 25 to 500 milligrams of a-ethyl-a-methylsuccinimide per dosage unit and a pharmaceutical carrier.

2. A composition in dosage unit form for the treatment of epilepsy comprising about 25 to 500 milligrams of u-ethyl-ot-IIlfillhYlSllCCiBll'IlldG per dosage unit and a liquid pharmaceutical carrier.

3. A composition in dosage unit form for the treatment of epilepsy comprising a gelatin capsule containing about 25 to 500 milligrams of u-ethyl-a-methylsuccinirnide.

4. A composition in dosage unit form for the treatment of epilepsy comprising a solid pharmaceutical carrier and about 25-to 500 milligrams of a-etl1yl-a-methylsuccinimide per dosage unit.

5. A tableted composition in dosage unit form for the treatment of epilepsy comprising a solid pharmaceutical carrier and about 25 to 500 milligrams of ot-BthYl-amethylsuccinimide per dosage unit. H 6. An encapsulated composition in dosage unit form for the treatment of epilepsy comprising a solid pharma ceutical carrier and about 25 to 500 milligrams of m-ethyla-methylsuccinimide per dosage unit.

7. A method 'for the treatment of petit mal epilepsy which comprises administering u-ethyl-a-methylsuccinimide to a human patient.

8. A method for the treatment of petit mal epilepsywhich comprises administering a-ethyl-a-methylsuccinimide to a human patient in a daily oral dose of from 100 milligrams to 5 grams. v

9. A method for the treatment of petit mal epilepsy which comprises administering a composition comprising not less than five percent of wethyl-a-methylsuccinimide to a human patient in a daily oral dose which provides from 100 milligrams to 5 grams of the said a-ethyl-ctmethylcuccinimide.

References Cited in the file of this patent UNITED STATES PATENTS 2,614,106 Stoughton Oct. 14, 1952 2,643,257 Miller Iune23, 1953 2,643,258 Miller June 23, 1953 2,643,259 Miller June 23, 1953 OTHER REFERENCES Sircart Vol. 125, J. Chem. Soc., pp. 600, 1254 (1927). 

1. A COMPOSITION IN DOSAGE UNIT FORM FOR THE TREATMENT OF EPILEPSY COMPRISING ABOUT 25 TO 500 MILLIGRAMS OF A-ETHYL-A-METHYLSUCCINIMIDE PER DOSAGE UNIT AND A PHARMACEUTICAL CARRIER. 